High enhancer-loading polyacrylate formulation for transdermal applications

ABSTRACT

A polyacrylate formulation suitable for delivery of drug to through a body surface of an individual. By loading the drug and permeation enhancers at a high concentration into a polyacrylate proadhesive that has inadequate adhesive properties for typical adhesive application on the skin, a formulation with desirable adhesive characteristics and effective therapeutic properties can be made. The proadhesive has higher glass transition temperature than typical pressure sensitive adhesives.

CROSS REFERENCE TO RELATED U.S. APPLICATION DATA

The present application is derived from and claims priority toprovisional application U.S. Ser. No. 60/720,201, filed Sep. 23, 2005,and provisional application U.S. Ser. No. 60/723,135, filed Sep. 30,2005, which are herein incorporated by reference in their entireties.

TECHNICAL FIELD

This invention relates to transdermal drug delivery using a formulationhaving a polyacrylate. In particular, the invention relates to adhesivesystems with polyacrylate having high enhancer and drug tolerance whenused in transdermal drug delivery.

BACKGROUND

Transdermal devices for the delivery of biologically active agents havebeen used for maintaining health and therapeutically treating a widevariety of ailments. For example, analgesics, steroids, etc., have beendelivered with such devices. Such transdermal devices include patches inwhich a biologically active agent is delivered to the body tissuepassively without use of an additional energy source. Many such deviceshave been described, for example, in U.S. Pat. Nos. 3,598,122,3,598,123, 4,379,454, 4,286,592, 4,314,557, 4,568,343, and U.S.Application No. 2003002682, all of which are incorporated herein byreference.

A transdermal patch is typically a small adhesive bandage that containsthe drug to be delivered. A simple type of such transdermal patches isan adhesive monolith including a drug-containing reservoir disposed on abacking. The reservoir is typically formed from a pharmaceuticallyacceptable pressure sensitive adhesive. In some cases, the reservoir canbe formed from a non-adhesive material, the skin-contacting surface ofwhich is provided with a thin layer of a suitable adhesive. The rate atwhich the drug is administered to the patient from these patches canvary due to normal person-to-person and skin site-to-skin sitevariations in the permeability of skin to the drug.

Sometimes patches can be multilaminate or can include a liquid reservoirlayer in the patches. A drug release-rate controlling membrane can bedisposed between the drug reservoir and the skin-contacting adhesive.This membrane, by decreasing the release rate of drug from the patch,serves to reduce the effects of variations in skin permeability.

Although the transdermal delivery of therapeutic agents has been thesubject of intense research and development for over 30 years, only arelatively small number of drug molecules are suitable for transdermaldelivery due to the fact that human skin is an excellent barrier.Various techniques have been explored to enhance the permeation of drugmolecules that are not otherwise suitable for transdermal delivery. Ofthese techniques, chemical enhancement is the most established and iscurrently employed commercially. Pressure sensitive adhesives, such asacrylic adhesives, are used in most transdermal drug delivery devices asa means of providing intimate contact between the drug delivery deviceand the skin. The use of enhancers, especially at high concentrations,usually has a significant impact on the properties of pressure sensitiveadhesives, such as cohesive strength, adhesive flow, tackiness andadhesion strength. Therefore, pressure sensitive adhesives have to bedesigned in a way that they can provide the needed performance in thepresence of enhancer.

Many systems with adhesives and permeation enhancers have been describedin the past, e.g., U.S. Pat. Nos. 3,558,574; 4,554,324; 4,822,676;5,573,778, and 6,077,527. Some discussed the use of grafting macromersto the backbone (U.S. Pat. Nos. 5,573,778). Some discussed cross-linking(U.S. Pat. No. 6,077,527). However, at the present, there does not seemto be systems that have high enhancer and drug tolerance and yetprovides pressure sensitive adhesive property.

There continues to be a need for improved transdermal systems,especially transdermal systems that can deliver pharmaceutical agentswith a high load of pharmaceutical agents and/or permeation enhancersand yet provide desirable pressure sensitive property.

SUMMARY

The present invention provides a method and a device for transdermaldelivery of biologically active agent or agents for therapeutic effects,especially delivery of the biologically active agents to a subjectthrough skin or other body surface that is accessible from exteriorwithout using endoscopic devices. An individual can wear the device overan extended period of time.

In one aspect, the present invention provides a transdermal systemhaving improved enhancer loading, little or no cold flow, with desirabletack and adhesion.

In another aspect, the present invention relates to a transdermal systemin which pharmaceutical properties, in particular, enhancer tolerance,is optimized by controlling the rheological properties of thepolyacrylate material.

In one aspect of the invention, a novel technique is provided forincreasing adhesive enhancer tolerance. Specifically, it has beendiscovered that by increasing the glass transition temperature of theacrylate polymer using the ratio of soft monomer and hard monomer, it ispossible to load enhancer concentrations into the polymer at a highweight percent to obtain a formulation and still achieve desirableadhesive characteristics. It is possible to load drug and/or enhancerinto the polymer composition to a high concentration, e.g., at greaterthan 20 dry weight %, greater than 30 dry weight % (or solids wt %),even up to 40-50 wt %, without adversely impacting the adhesion andrheological characteristics for pressure sensitive adhesive (PSA)application. With sufficient loadings of permeation enhancers in suchformulations, sustained high rates of drug delivery can be achieved.With adequate adhesive properties, the resulting reservoir withsufficient drug loading and permeation enhancers can be used foreffective therapeutic results. Prior to incorporation of drugs andingredients, the polymeric materials are not suitable PSAs “as is”because of the stiffness of the polymer and insufficient adhesiveness ortackiness. These polymeric materials become adhesive and have thedesired PSA characteristics after incorporating drug, permeationenhancer and optionally other ingredients in suitable quantities. Suchpolymeric materials, which are not suitable as a PSA as is (prior toincorporation of drugs and ingredients) but will have the desired PSAcharacteristics after incorporating drugs and/or other ingredients, canbe called “proadhesive” herein.

In one aspect, the transdermal drug delivery device of the presentinvention has a reservoir including at least one drug, permeationenhancer and an acrylate polymer, wherein the acrylate polymer has nomore than 60 wt % soft monomer, has at least 40 wt % hard monomer and 10to 35 wt % polar functional monomer, the acrylate polymer constituting45 wt % to 80 wt % of the reservoir. The acrylate polymer can havedissolved in it at least 30 wt % of the drug and permeation enhancercombination. The acrylate polymer has a T_(g) of greater than −15° C. ifwithout permeation enhancer and without drug. With drug and enhancersdissolved therein, the reservoir has pressure sensitive adhesiveproperties applicable to the body surface for transdermal delivery.

In another aspect, the present invention provides methods of making andusing such transdermal drug delivery devices.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cross-section through a schematic, perspective viewof one embodiment of a transdermal therapeutic system according to thepresent invention.

FIG. 2 illustrates a cross-section view through another embodiment of atransdermal therapeutic system of this invention.

DETAILED DESCRIPTION

The present invention relates to transdermal delivery of pharmaceuticalagents to a patient in need thereof involving the use of an acrylatepolymer material that after incorporating drug(s) and other ingredientstherein can act as a pressure sensitive adhesive (PSA) and maintain thetransdermal delivery system on a body surface of an individual.

A pressure sensitive adhesive (PSA) is a material that adheres withlight pressure, is aggressively and permanently tacky, exerts a strongholding force, and should be removable without leaving a residue.Pressure sensitive tack is the property that enables an adhesive to forma bond with the surface of another material upon brief contact underlight pressure (usually no more than applied finger pressure). Toachieve pressure sensitive tack, adhesives have to be easily deformed atthe time scale allowed for bond formation, usually on the order of afraction of a second. Besides tack, cohesive strength is desirable intransdermal uses to reduce the mass transfer of adhesive to the skinwhen the patch is removed. Resistance to cold flow is also desirable toprevent the adhesive from oozing from the patch during storage and use.It was found that the glass transition temperature, creep compliance(J), and elastic modulus (G′) at the application temperature areimportant requirements for pressure sensitive adhesive performance.

Traditionally a transdermal drug delivery system was formulated with apressure sensitive adhesive that has a glass transition temperature(T_(g)) in the range of −40° C. to −10° C. According to the presentinvention, the starting acrylate polymeric material (which can beformulated into an adhesive material having pharmaceuticals (or drugs)and/or enhancers) preferably has a glass transition temperature (T_(g))in the range of about −15° C. or higher, more preferably −15° C. to 0°C., and even more preferably −10° C. to 0° C.; creep compliance of about7×10⁻⁵ cm²/dyn (at 3600 second) or below, and modulus G′ of about 8×10⁵dyn/cm² or above. The polymeric material can be formulated into atransdermal reservoir matrix (including carrier structure) with acombined drug and/or enhancer concentration greater than 30 dry weightpercent (wt %), or even greater than 40 dry weight percent. Theresulting transdermal adhesive formulation with drug agent(s) and/orenhancers will provide excellent adhesion with no cold flow, i.e., withno cold flow of an amount that is noticeable and would affect the normaluse of the delivery system. By contrast, the starting proadhesiveacrylate polymer has poor adhesive properties because the glasstransition temperature is too high. Once plasticized in the transdermalformulation, the glass temperature drops into the pressure sensitiverange, about −10 to −40° C., and the resulting creep compliance andstorage modulus enables the achievement of good tack, with little or nocold flow. Creep compliance is an important parameter to evaluate coldflow behavior of a pressure sensitive adhesive (PSA). In a transdermaldrug delivery system, if the creep compliance is large, the adhesivewill have cold flow with time, i.e., the adhesive may loose its shapejust because of the weight of the material in the device under gravity.

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below. As used inthis specification and the appended claims, the singular forms “a,” “an”and “the” include plural references unless the text content clearlydictates otherwise.

As used herein, the term “transdermal” refers to the use of skin,mucosa, and/or other body surfaces as a portal for the administration ofdrugs by topical application of the drug thereto for passage into thesystemic circulation.

“Biologically active agent” is to be construed in its broadest sense tomean any material that is intended to produce some biological,beneficial, therapeutic, or other intended effect, such as enhancingpermeation, relief of pain and contraception. As used herein, the term“drug” refers to any material that is intended to produce somebiological, beneficial, therapeutic, or other intended effect, such asrelief of symptoms of health disorder, but not agents (such aspermeation enhancers) the primary effect of which is to aid in thedelivery of another biologically active agent such as the therapeuticagent transdermally.

As used herein, the term “therapeutically effective” refers to theamount of drug or the rate of drug administration needed to produce thedesired therapeutic result. As used herein, the term “permeationenhancement” intends an increase in the permeability of skin to a drugin the presence of a permeation enhancer as compared to permeability ofskin to the drug in the absence of a permeation enhancer. A“permeation-enhancing amount” of a permeation-enhancer is an amount ofthe permeation enhancer sufficient to increase the permeability of thebody surface of the drug to deliver the drug at a therapeuticallyeffective rate.

“Acrylate”, “polyacrylate” or “acrylic polymer”, when referring to apolymer for an adhesive or proadhesive, refers to polymer or copolymerof acrylic acid, ester(s) thereof, acrylamide, or acrylonitrile. Unlessspecified otherwise, it can be a homopolymer, copolymer, or a blend ofhomopolymers and/or copolymers.

As used in the present invention, “soft” monomers refer to the monomersthat have a T_(g) of about −80 to −10° C. after polymerization intohomopolymer; “hard” monomers refer to the monomers that have a T_(g) ofabout 0 to 250° C. after forming homopolymer; and “functional” monomersrefer to the monomers that contain hydrogen bonding functional groupssuch as hydroxyl, carboxyl or amino groups (e.g., alcohols, carboxylicacid, or amines), these polar groups tend to increase the hydrophilicityof the acrylate polymer and increase polar drug solubility.

Exemplary transdermal drug delivery systems of the present invention areillustrated by the embodiments shown in FIGS. 1 and 2. As shown in FIGS.1 and 2, an embodiment of the transdermal monolithic patch 1 accordingto this invention has a backing layer 2, a drug reservoir 3 disposed onthe backing layer 2, and a peelable protective layer 5. In the reservoir3, which can be a layer, at least the skin-contacting surface 4 is anadhesive. The reservoir is a matrix (carrier) that is suitable forcarrying the pharmaceutical agent (or drug) for transdermal delivery.Preferably, the whole matrix, with drugs and other optional ingredients,is a material that has the desired adhesive properties. The reservoir 3can be either a single phase polymeric composition or a multiple phasepolymeric composition. In a single phase polymeric composition the drugand all other components are present at concentrations no greater than,and preferably less than, their saturation concentrations in thereservoir 3. This produces a composition in which all components aredissolved. The reservoir 3 is formed using a pharmaceutically acceptablepolymeric material that can provide acceptable adhesion for applicationto the body surface. In a multiple phase polymeric composition, at leastone component, for example, a therapeutic drug, is present in amountmore than the saturation concentration. In some embodiments, more thanone component, e.g., a drug and a permeation enhancer, is present inamounts above saturation concentration. In the embodiment shown in FIG.1, the adhesive acts as the reservoir and includes a drug.

In the embodiment shown in FIG. 2, the reservoir 3 is formed from amaterial that does not have adequate adhesive properties if without drugor permeation enhancer. In this embodiment of a monolithic patch 1, theskin-contacting surface of the reservoir 4 may be formulated with a thinadhesive coating 6. The reservoir 3 may be a single phase polymericcomposition or a multiple phase polymeric composition as describedearlier, except that it may not contain an adhesive with adequateadhesive bonding property for skin. The adhesive coating can contain thedrug and permeation enhancer, as well as other ingredients.

The backing layer 2 may be formed from any material suitable for makingtransdermal delivery patches, such as a breathable or occlusive materialincluding fabric or sheet, made of polyvinyl acetate, polyvinylidenechloride, polyethylene, polyurethane, polyester, ethylene vinyl acetate(EVA), polyethylene terephthalate, polybutylene terephthalate, coatedpaper products, aluminum sheet and the like, or a combination thereof.In preferred embodiments, the backing layer includes low densitypolyethylene (LDPE) materials, medium density polyethylene (MDPE)materials or high density polyethylene (HDPE) materials, e.g., SARANEX(Dow Chemical, Midland, Mich.). The backing layer may be a monolithic ora multilaminate layer. In preferred embodiments, the backing layer is amultilaminate layer including nonlinear LDPE layer/linear LDPElayer/nonlinear LDPE layer. The backing layer can have a thickness ofabout 0.012 mm (0.5 mil) to 0.125 mm (5 mil); preferably about 0.025 mm(1 mil) to 0.1 mm (4 mil); more preferably about 0.0625 mm (1.5 mil) to0.0875 mm (3.5 mil).

The drug reservoir 3 is disposed on the backing layer 2. At least theskin-contacting surface of the reservoir is adhesive. As mentioned, theskin-contacting surface can have the structure of a layer of adhesive.The reservoir 3 may be formed from drug (or biological active agent)reservoir materials as known in the art. For example, the drug reservoiris formed from a polymeric material in which the drug has reasonablesolubility for the drug to be delivered within the desired range, suchas, a polyurethane, ethylene/vinyl acetate copolymer (EVA), acrylate,styrenic block copolymer, and the like. In preferred embodiments, thereservoir 3 is formed from a pharmaceutically acceptable adhesive orproadhesive, preferably acrylate copolymer-based, as described ingreater detail below. The drug reservoir or the matrix layer can have athickness of about 1-10 mils (0.025-0.25 mm), preferably about 2-5 mils(0.05-0.12 mm), more preferably about 2-3 mils (0.05-0.075 mm).

Preferred materials for making the adhesive reservoir or adhesivecoating, and especially for making proadhesives according to the presentinvention include acrylates, which can be a copolymer of variousmonomers ((i) “soft” monomer, (ii) “hard” monomer, and optionally (iii)“functional” monomer) or blends including such copolymers. The acrylates(acrylic polymers) can be composed of a copolymer (e.g., a terpolymer)including at least two or more exemplary components selected from thegroup including acrylic acids, alkyl acrylates, methacrylates,copolymerizable secondary monomers or monomers with functional groups.Functional monomers are often used to adjust drug solubility, polymercohesive strength, or polymer hydrophilicity. Examples of functionalmonomers are acids, e.g., acrylic acid, methacrylic acid andhydroxy-containing monomers such as hydroxyethyl acrylate, hydroxypropylacrylate, acrylamides or methacrylamides that contain amino group andamino alcohols with amino group protected. Functional groups, such asacid and hydroxyl groups can also help to increase the solubility ofbasic ingredients (e.g., drugs) in the polymeric material. Additionaluseful “soft” and “hard” monomers include, but are not limited to,methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate,methoxyethyl methacrylate, and the like. Additional examples of acrylicadhesive monomers suitable in the practice of the invention aredescribed in Satas, “Acrylic Adhesives,” Handbook of pressure-SensitiveAdhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van NostrandReinhold, New York (1989). Examples of acrylic adhesives arecommercially available from National Starch and Chemical Company,Bridgewater, N.J.

The acrylate polymers can include cross-linked and non-cross-linkedpolymers. The polymers can be cross-linked by known methods to providethe desired polymers. However, cross-linking is hard to control and mayresult in polymeric materials that are too stiff or too soft. Accordingto the present invention, it is preferred that the polymeric materialfor incorporation of drugs and other ingredients to be polymer withoutcrosslinking and no cross-linking agent is used in forming the polymericmaterial. It is further preferred that the monomers do not selfcross-link during polymerization. In the present invention, it was foundthat, instead of cross-linking to form a matrix adhesive with desiredPSA properties for incorporating drugs and enhancers, good control ofthe PSA properties can be achieved by selecting polymeric materials thatare too stiff prior to incorporation of drugs and other ingredients andsubsequently incorporating such drugs and ingredients. It has been foundthat an acrylate polymer composition with a creep compliance (J) of7×10⁻⁵ cm²/dyn or below and elastic modulus G′ of 8×10⁵ dyn/cm² orabove, although too stiff as a PSA as is, after formulating with drug orenhancer or a combination thereof at a relative high concentration willachieve the desirable adhesive properties. The plasticizing ortackifying effect of the drug(s) and/or other ingredients on thepolymeric material provides a means to achieve the desired adhesiveproperties in the reservoir.

Acrylate polymers, when the main monomer of which has the generalformula CH₂═CH—COOR, are particularly useful as proadhesives. Typicalmain monomers are normally alkyl acrylates of 4 to 1 carbon atoms,preferably 4-10 carbons. Useful alkyl acrylates include ethyl acrylate,butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate,octyl acrylate, isooctyl acrylate, decyl acrylate, dodecyl acrylates,with 2-ethylhexyl acrylate, butyl acrylate, and iso-octyl acrylate beingpreferred. Such “soft” monomers if polymerized into homopolymergenerally have a T_(g) of less than about 0° C., preferably about −10°C. to −80° C., preferably about −20° C. to −80° C. Preferably, they arepresent in an amount of about 10 to 70 wt % (i.e., dry weight % orsolids wt %), more preferably no more than about 60% by weight, morepreferably no more than about 50 wt % of the total monomer weight andmore preferably about 40 to 50 wt %. As used herein, when a monomer issaid to be present in the acrylate polymer at a certain percentage, itis meant that the monomer has been polymerized in the acrylate polymerat that percentage of polymerization monomer ingredients.

“Hard” modifying monomers are mainly used to modify the adhesiveproperties, mainly glass transition temperature (e.g., to increase theT_(g) and to make the resulting polymer stiffer at room temperature), tomeet various application requirements. A hard monomer, if polymerizedinto homopolymer, has a T_(g) of about 0 to 250° C., preferably about 20to 250° C., more preferably in the range of about 30 to 150° C. (forconvenience, this is referred to as the “homopolymer T_(g) ” herein).The hard monomer component (or content in the polymer) is present in anamount of about 10 wt % or more, preferably in the range of about 30 to60 wt %, preferably about 35 to 60 wt %, more preferably about 40 to 60wt %, even more preferably about 40 to 50 wt % in the polymerization.Examples of hard modifying monomers are methyl acrylate, vinyl acetate,methyl methacrylate, isobutyl methacrylate, vinyl pyrrolidone,substituted acrylamides or methacrylamides. Homopolymers of thesemonomers generally have higher glass transition temperature thanhomopolymers of the soft monomers.

Certain nitrogen containing monomers can be included in thepolymerization to raise the T_(g). These include N-substitutedacrylamides or methacrylamides, e.g., N-vinyl pyrrolidone, N-vinylcaprolactam, N-tertiary octyl acrylamide (t-octyl acrylamide), dimethylacrylamide, diacetone acrylamide, N-tertiary butyl acrylamide (t-butylacrylamide and N-isopropyl acrylamide (i-propyl acrylamide). Furtherexamples of monomers that can be used in polymerization to modify andraise the T_(g) of the polymer include cyanoethylacrylates, N-vinylacetamide, N-vinyl formamide, glycidyl methacrylate and allyl glycidylether.

Functional monomers can be used to either provide needed functionalityfor solubilizing agents in the polyacrylate or improve cohesiveproperties. Examples of functional monomers are organic acids, e.g.,acrylic acid, methacrylic acid, and hydroxyl-containing monomers such ashydroxyethyl acrylate. Preferred functional monomers when incorporatedinto the polymer result in acid groups, i.e., —COOH, hydroxyl groups,i.e., —OH, or amino groups in the polymer for affecting the solubilityof basic agents such as basic drugs. Examples of hydroxy functionalmonomers include hydroxyethyl acrylate, hydroxypropyl acrylate,hydroxyethyl methacrylate and hydroxypropyl methacrylate. The hydroxylgroups can be primary, secondary or tertiary hydroxyl. In some cases,the acrylate polymer can includes at least one non-primary hydroxylfunctional monomer component to provide orientation of the functionalgroup in the polymer. Suitable non-primary hydroxyl functional monomersare secondary hydroxyl functional monomers such as hydroxypropylacrylate. Useful carboxylic acid monomers to provide the functionalgroup preferably contain from about 3 to about 6 carbon atoms andinclude, among others, acrylic acid, methacrylic acid, itaconic acid,and the like. Acrylic acid, methacrylic acid and mixtures thereof areparticularly preferred as acids.

A functional monomer can also be a hard monomer, if its homopolymer hasthe high T_(g). Such functional monomers that can also function as hardmonomers include, e.g., hydroxyethyl acrylate, hydroxypropyl acrylate,acrylic acid, dimethylacrylamide, dimethylaminoethyl methacrylate,tert-butylaminoethyl methacrylate, methoxyethyl methacrylate, and thelike.

The functional monomer(s) are preferably present in the acrylate polymerin an amount of about at least 5 wt %, preferably at least 10 wt %,preferably 10 to 40 wt %, more preferably about 10 to 30 wt %, morepreferably about 10 to 20 wt %, even more preferably 10 to 15 wt %, eventhough some of the functional monomer(s) may be hard monomers. Examplesof preferred functional monomer component include acrylic acid andhydroxyethyl acrylate, acrylamides or methacrylamides that contain aminogroup and amino alcohols with amino group protected. One of theapplications of using functional monomers is to make a polar proadhesivehaving higher enhancer tolerance, in that, for example, the resultingPSA with the enhancers and/or drug will not phase separate or haveexcessive cold flow.

In certain embodiments, the hard monomer(s) that are not also functionalmonomer can constitute about 10 to 60 wt %, preferably about 40 to 60 wt% of the acrylate monomer, especially in cases in which no acidicfunctional hard monomer and less than about 20 wt % of hydroxylfunctional hard monomer are included in the acrylate polymer. In otherembodiments, the hard monomer(s) that are not also functional monomercan constitute about 5 to 15 wt %, e.g., about 10 wt % of the acrylatemonomer, especially in cases in which a large amount (e.g., about 25 wt% or more) of functional hard monomer(s) are included, such as when morethan about 5 wt % acidic hard functional monomers and 10 or more wt %(e.g., about 10-25 wt %) hydroxyl functional hard monomer(s) areincluded in the acrylate polymer.

Below is a table showing the T_(g)'s of exemplary soft and hardhomopolymers the monomers of which are useful for making proadhesive ofthe present invention. Some of the monomers (e.g., acrylic acid,hydroxyethyl acrylate) are also functional monomers.

poly(hydroxyethyl acrylate) (hard/functional around 100° C. monomer)poly(acrylic acid) (hard/functional monomer) 106° C. poly(vinyl acetate)(hard monomer) 30° C. poly(ethylhexyl acrylate) (soft monomer) −70° C.poly(isopropyl acrylate) (soft monomer) −8° C. poly(n-propyl acrylate)(soft monomer) −52° C. poly(isobutyl acrylate) (soft monomer) −40° C.poly(n-butyl acrylate) (soft monomer) −54° C. poly(n-octyl acrylate)(soft monomer) −80° C.

It has been found that the soft monomers 2-ethylhexyl acrylate and butylacrylate are especially suitable to polymerize with functional monomershydroxyethyl acrylate or acrylic acid either alone or in combination toform the acrylate polymer of the present invention. Further, the hardmonomer vinyl acetate has been found to be very useful to polymerizewith the soft monomers 2-ethylhexyl acrylate and butyl acrylate, eitheralone or in combination to form the proadhesive. Thus, the acrylateproadhesive polymer of the present invention is especially suitable tobe made from 2-ethylhexyl acrylate or butyl acrylate copolymerized withhydroxyethyl acrylate, acrylic acid, or vinyl acetate, either alone orin combination. Another preferred hard monomer is t-octyl acrylamide,which can be used alone or in combination with other hard monomers suchas acrylic acid and hydoxyethyl acrylate.

In an embodiment, the proadhesive is made by polymerizing monomersincluding about 30 to 75 wt % vinyl acetate, about 10-40 wt % hydroxylfunctional monomer and about 10-70 wt % soft monomer such as2-ethylhexyl acrylate or butyl acrylate. In a preferred embodiment, theproadhesive is made by polymerizing monomers including about 50 to 60 wt% vinyl acetate, about 10-20 wt % hydroxyethyl acrylate, and about 20-40wt % 2-ethylhexyl acrylate. In some cases, no carboxyl (acid) group isused. Hydroxyethyl acrylate or hydroxypropyl acrylate can be used toprovide hydroxyl functionality. For example, one embodiment is aproadhesive having about 50 wt % vinyl acetate, about 10 wt %hydroxyethyl acrylate, and about 40 wt % 2-ethylhexyl acrylate. As usedherein, when a specific percentage is mentioned, it is contemplatedthere may be slight variations, e.g., of plus or minus 5% of thespecific percentage (i.e., about 10 wt % may included 10 wt %±0.5wt %).One other embodiment is a proadhesive having about 60 wt % vinylacetate, about 20 wt % hydroxyethyl acrylate, and about 20 wt %2-ethylhexyl acrylate.

In another embodiment, the proadhesive is made by polymerizing monomersincluding both monomer with hydroxyl group and monomer with carboxylgroup. For example, certain preferred monomer combination forpolymerization include an alkyl acrylate, an acrylamide, a monomer withhydroxyl group and a monomer with carboxyl group, e.g., making aproadhesive by polymerizing butyl acrylate, 2-hydroxyethyl acrylate or 2hydroxypropyl acrylate or hydroxypropyl methacrylate, t-octylacrylamide, and acrylic acid. In an embodiment, greater than 3 wt % of ahydroxypropyl acrylate or hydroxylpropyl methacrylate is used in makingthe acrylate polymer.

In certain cases for making a proadhesive in which both monomers withhydroxyl groups and monomer with carboxyl groups are to be polymerizedwith a soft monomer, e.g., butyl acrylate, the monomer proportions inthe polymerization includes about 55 to 65 wt % soft monomer (e.g.,butyl acrylate), about 5 to 15 wt % t-octyl acrylamide, about 20 to 30wt % hydroxyethyl or hydroxypropyl acrylate and about 5 to 10 wt % acidmonomer such as acrylic acid. In one embodiment, the acrylate polymerincludes about 59 wt % butyl acrylate, about 10 wt % t-octyl acrylamide,about 25 wt % hydroxypropyl acrylate and about 6 wt % acrylic acid. Inanother embodiment, the hydroxypropyl acrylate is replaced withhydroxyethyl acrylate.

It is important that with the incorporation of a large amount ofpermeation enhancers, the T_(g) of the resulting reservoir (with thedrug, permeation enhancers and other ingredients) is such that theresulting reservoir would have good PSA properties for application tothe body surface of an individual. Further, the resulting reservoirshould not have cold flow that affects the normal application of thetransdermal delivery. The acrylate polymer (or a blend of acrylatepolymers) constitutes preferably about 40 wt % to 90 wt %, morepreferably about 45 wt % to 80 wt % of the reservoir. It is possible toload drug and/or enhancer into the polymer composition to a highconcentration. For example, the permeation enhancer, with or withoutdrug, can be at or greater than about 20 dry weight %, preferably at orgreater than about 30 dry weight % (or solids wt %), even morepreferably up to about 40 to 50 wt % of the drug delivery reservoir,without adversely impacting the adhesion and rheological characteristicsfor pressure sensitive adhesive (PSA) application.

Preferred acrylate polymers or blends thereof provide the acrylicpressure sensitive properties in the delivery system glass transitiontemperature of about −10 to −40° C., preferably about −20 to −30° C. atapplication on a surface. The T_(g) of an acrylate polymer can bedetermined by differential scanning calorimetry (DSC) known in the art.Also, theoretical ways of calculating the T_(g) of acrylate polymers arealso known. Thus, one having a sample of an acrylate polymer will beable to experimentally determine the T_(g), for example, by DSC. One canalso determine the monomer composition of the acrylate polymer andestimate theoretically the T_(g) by calculation. From the knowledge ofthe monomer composition of an acrylate polymer having drugs andenhancers, one can also make the acrylate polymer without the drug andenhancer and determine the T_(g). According to the present invention,the acrylate materials, before dissolving the drug(s), permeationenhancers, etc., have T_(g)'s that are in the range of about −20 to 10°C., and have rheological properties that are not quite suitable for usedirectly as a PSA to skin because of the stiffness of the material. Theacrylate polymers preferably have a molecular weight in a range of about200,000 to 600,000. Molecular weight of acrylate polymers can bemeasured by gel permeation chromatography, which is known to thoseskilled in the art.

To control the physical characteristics of the acrylate polymer and thepolymerization, it is preferred that monomers of molecular weight ofbelow 500, even more preferably below 200 be used in the polymerization.Further, although optionally larger molecular weight monomers (linearmacromonomers such as ELVACITE™ from ICI) can be used in thepolymerization, it is preferred that they are not used. Thus, preferablyno monomer of molecular weight (MW) above 5000, more preferably nomonomer of MW above 2000, even more preferably no monomer of MW above500, is to be included in the polymerization to form the acrylatepolymer. Thus, in the present invention, preferably, proadhesivepolymers can be formed without macromonomers, or substantially withoutmacromonomers, to have adhesive properties too stiff for PSA as iswithout incorporation of a large amount of permeation enhancers anddrug. However, such proadhesives will become suitable for adhering tothe skin as PSA in patch application after the appropriate amount ofpermeation enhancer and drug are dissolved therein.

However, if desired, in certain embodiments, optionally, the reservoircan include diluent materials capable of reducing quick tack, increasingviscosity, and/or toughening the reservoir structure, such aspolybutylmethacrylate (ELVACITE, manufactured by ICI Acrylics, e.g.,ELVACITE 1010, ELVACITE 1020, ELVACITE 20), polyvinylpyrrolidone, highmolecular weight acrylates, i.e., acrylates having an average molecularweight of at least 500,000, and the like.

The acrylate polymers of the present invention can dissolve a largeamount of permeation enhancer and allow the resulting drug andpermeation enhancer-containing adhesive to have the desired adhesive andcohesive property without the drug or permeation enhancer separating outof the acrylate polymer matrix either as crystals or as oil. Theresulting composition will be in the T_(g) and compliance range that itcan be applied to a body surface without leaving an undesirable amountof residue material on the body surface upon removal of the device. Thepreferred acrylate polymer is not cross-linked. It is contemplated,however, that if desired, a nonsubstantial amount of cross-linking maybe done, so long as it does not change substantially the T_(g), creepcompliance and elastic modulus of the acrylate polymer. It is also foundthat higher T_(g) and higher molecular weight of the acrylate areimportant for the acrylate polymer tolerating high enhancer loading.Since the measurement of the molecular weight of an acrylate polymer isdifficult, precise or definite values are often not obtainable. Morereadily obtainable parameters that are related to molecular weight anddrug and enhancer tolerance (i.e., solubility) are creep compliance andelastic modulus.

Enhancers typically behave as plasticizers to acrylate adhesives. Theaddition of an enhancer will result in a decrease in modulus as well asan increase in creep compliance, the effect of which is significant athigh enhancer loading. A high loading of enhancers will also lower theT_(g) of the acrylate polymer. Thus, to achieve a proadhesive that istolerant of high enhancer loading, other than increasing the T_(g) byusing a higher ratio of hard monomer to soft monomer and the selectionof suitable monomers, it is desirable to provide suitable highermolecular weight such that chain entanglement would help to achieve thedesirable theology. As a result, selecting a higher T_(g) and highermolecular weight for a proadhesive will increase the elastic modulus anddecrease the creep compliance of the acrylate, making the proadhesivemore enhancer tolerant. The measurement of the molecular weight of anacrylate polymer is often method-dependant and is strongly affected bypolymer composition, since acrylate polymers discussed here are mostlycopolymers, not homopolymers. More readily obtainable parameters thatrelate to molecular weight and drug and enhancer tolerance (i.e.,solubility) are creep compliance and elastic modulus.

According to the present invention, especially useful polymericmaterials for forming drug-containing PSA are acrylate polymers that,before the incorporation of drugs, enhancers, etc., and otheringredients for transdermal formation, have creep compliance (measuredat 30° C. and 3600 second) of about 7×10⁻⁵ cm²/dyn or below and storagemodulus G′ about 8×10⁵ dyn/cm² or above. Preferably the creep complianceis about 6×10⁻⁵ cm²/dyn to 2×10⁻⁶ cm²/dyn, more preferably about 5×10⁻⁵cm²/dyn to 4×10⁻⁶ cm²/dyn. Preferably the storage modulus is about 8×10⁵dyn/cm² to 5×10⁶ dyn/cm², more preferably about 9×10⁵ dyn/cm² to 3×10⁶dyn/cm². Such creep compliance and modulus will render these acrylatepolymers too stiff and unsuitable “as is” for dermal PSA applications.However, it was found that after formulating into a transdermal systemwith drugs, permeation enhancers, and the like, which produceplasticizing effect as well as tackifying effect, the acrylate polymersplasticized with permeation enhancers and/or drug would have a desirablestorage modulus and creep compliance that are suitable for transdermalPSA applications. For example, the plasticized material would have aresulting creep compliance that is about 1×10⁻³ cm²/dyn or less,preferably more than about 7×10⁻⁵ cm²/dyn, preferably from about 7×10⁻⁵cm²/dyn to 6×10⁻⁴ cm²/dyn, more preferably about 1×10⁻⁴ cm²/dyn to6×10⁻⁴ cm²/dyn. The preferred storage modulus of the plasticizedacrylate polymer is about 1×10⁵ dyn/cm² to 8×10⁵ dyn/cm², preferablyabout 1.2×10⁵ dyn/cm² to 6×10⁵ dyn/cm², more preferably about 1.4×10⁵dyn/cm² to 5×10⁵ dyn/cm².

It was found that incorporating the proper selection of drug and otheringredients (such as permeation enhancers) and using the appropriateamounts thereof can change the T_(g), storage modulus G′ and creepcompliance to result in an effective transdermal drug delivery systemwith the right adhesive properties for the desirable length of time,such as 24 hours, 3 day, or even 7 day application on a body surface.Such transdermal drug delivery systems will have little or no cold flow.As used herein, “little cold flow” means that any shape change of thedevice caused by cold flow is not noticeable by an average person onwhich the device is applied over the time of use. Particularly usefulfor forming adhesives incorporating an increased amount of beneficialagents (including drugs and permeation enhancers) over prior adhesivesin transdermal drug delivery are the acrylic formulations containing arelatively lower percentage of soft monomers. It has been found thatincreasing the molecular weight increases the modulus of elasticity anddecreases the polymer chain mobility via chain entanglements. Also,increasing hard monomer content increases the glass transitiontemperature.

As aforementioned, the reservoir 3 can include a single phase polymericcomposition, free of undissolved components, containing an amount of thedrug sufficient to induce and maintain the desired therapeutic effect ina human for, e.g., at least three days. The present invention hasutility in connection with the delivery of drugs within the broad classnormally delivered through body surfaces and membranes, including skin.In general, this includes therapeutic agents in all of the major areas,including, but not limited to, ACE inhibitors, adenohypophosealhormones, adrenergic neuron blocking agents, adrenocortical steroids,inhibitors of the biosynthesis of adrenocortical steroids,alpha-adrenergic agonists, alpha-adrenergic antagonists, selectNealpha-two-adrenergic agonists, analgesics, antipyretics andanti-inflammatory agents, androgens, local and general anesthetics,antiaddictive agents, antiandrogens, antiarrhythmic agents,antiasthmatic agents, anticholinergic agents, anticholinesterase agents,anticoagulants, antidiabetic agents, antidiarrheal agents, antidiuretic,antiemetic and prokinetic agents, antiepileptic agents, antiestrogens,antifungal agents, antihypertensive agents, antimicrobial agents,antimigraine agents, antimuscarinic agents, antineoplastic agents,antiparasitic agents, antiparkinson's agents, antiplatelet agents,antiprogestins, antischizophrenia agents, antithyroid agents,antitussives, antiviral agents, atypical antidepressants,azaspirodecanediones, barbituates, benzodiazepines, benzothiadiazides,beta-adrenergic agonists, beta-adrenergic antagonists, selectivebeta-one-adrenergic antagonists, selective beta-two-adrenergic agonists,bile salts, agents affecting volume and composition of body fluids,butyrophenones, agents affecting calcification, calcium channelblockers, cardiovascular drugs, catecholamines and sympathomimeticdrugs, cholinergic agonists, cholinesterase reactivators, contraceptiveagents, dermatological agents, diphenylbutylpiperidines, diuretics,ergot alkaloids, estrogens, ganglionic blocking agents, ganglionicstimulating agents, hydantoins, agents for control of gastric acidityand treatment of peptic ulcers, hematopoietic agents, histamines,histamine antagonists, hormones, norelgestromin, 5-hydroxytryptamineantagonists, drugs for the treatment of hyperlipoproteinemia, hypnoticsand sedatives, immunosupressive agents, laxatives, methylxanthines,moncamine oxidase inhibitors, neuromuscular blocking agents, organicnitrates, opiod analgesics and antagonists, pancreatic enzymes,phenothiazines, progestins, prostaglandins, agents for the treatment ofpsychiatric disorders, retinoids, sodium channel blockers, agents forspasticity and acute muscle spasms, succinimides, thioxanthines,thrombolytic agents, thyroid agents, tricyclic antidepressants,inhibitors of tubular transport of organic compounds, drugs affectinguterine motility, vasodilators, vitamins and the like, alone or incombination. Basic drugs such as opioids (e.g., fentanyl and analogs:alfentanil, carfentanil, lofentanil, remifentanil, sufentanil,trefentanil, and the like), galantamine, and the salts and esters ofsuch basic drugs are well suited to be incorporated in the reservoirwith the acrylate polymer.

The drug can be included in the reservoir at an amount of about 1 to 20wt %, preferably about 2 to 15 wt %. With the aid of a large quantity ofpermeation enhancers in a reservoir of the present invention, many drugscan now be delivered through the body surface for therapeutic effect.

As indicated in the above, in some embodiments, the reservoir or theadhesive may contain additional components such as additives, permeationenhancers, stabilizers, dyes, diluents, plasticizer, tackifying agent,pigments, carriers, inert fillers, antioxidants, excipients, gellingagents, anti-irritants, vasoconstrictors and other materials as aregenerally known to the transdermal art. Typically, such materials arepresent below saturation concentration in the reservoir.

Permeation enhancers can be useful for increasing the skin permeabilityof the drug or drugs to achieve delivery at therapeutically effectiverates. Such permeation enhancers can be applied to the skin bypretreatment or currently with the drug, for example, by incorporationin the reservoir. A permeation enhancer should have the ability toenhance the permeability of the skin for one, or more drugs or otherbiologically active agents. A useful permeation enhancer would enhancepermeability of the desired drug or biologically active agent at a rateadequate to achieve therapeutic plasma concentrations from a reasonablysized patch (e.g., about 5 to 50 cm², although it may be larger). Someuseful permeation enhancers include non-ionic surfactants, one or morecan be selected from the group including glyceryl mono-oleate, glycerylmono-laurate, sorbitan mono-oleate, glyceryl tri-oleate, and isopropylmyristate. The non-ionic surfactant can be used in the amount of about0.1 to 30 wt % solids to the total composition of the reservoir layer.Examples of permeation enhancers include, but are not limited to, fattyacid esters of fatty acid esters of alcohols, including glycerin, suchas capric, caprylic, dodecyl, oleic acids; fatty acid esters ofisosorbide, sucrose, polyethylene glycol; caproyl lactylic acid;laureth-2; laureth-2 acetate; laureth-2 benzoate; laureth-3 carboxylicacid; laureth-4; laureth-5 carboxylic acid; oleth-2; glycerylpyroglutamate oleate; glyceryl oleate; N-lauroyl sarcosine; N-myristoylsarcosine; N-octyl-2-pyrrolidone; lauraminopropionic acid; polypropyleneglycol-4-laureth-2; polypropylene glycol-4-laureth-5dimethy-1 lauramide;lauramide diethanolamine (DEA). Preferred enhancers include, but are notlimited to, lauryl pyroglutamate (LP), glyceryl monolaurate (GML),glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate (GMO),oleic acid, N-lauryl sarcosine, ethyl palmitate, laureth-2, laureth-4,and sorbitan monolaurate. Additional examples of suitable permeationenhancers are described, for example, in U.S. Pat. Nos.: 5,785,991;5,843,468; 5,882,676; and 6,004,578.

In some embodiments, especially some in which the reservoir does notnecessarily have adequate adhesive properties and a separate adhesivelayer is used, a dissolution assistant can be incorporated in thereservoir to increase the concentration of the drug or biologicallyactive ingredient within the reservoir layer. As for the dissolutionassistant, one or more can be selected from the group includingtriacetin, isopropyl alcohol, propylene glycol, dimethylacetamide,propylene carbonate, diethylethanolamine, diethyl amine, triethylarnine,N-methyl morpholine, benzalkonium chloride, oleic acid, lactic acid,adipic acid, succinic acid, glutaric acid, sebacic acid, andhydroxycaprilic acid. Permeation enhnacers can also act assolubilization assistants.

As used herein, “permeation enhancers” is meant to include dissolutionassistants, unless specified otherwise in context. Permeation enhancers(not including dissolution assistants) can consititute up to about 35%solids by weight, preferably about 0.1 to 30% by weight and morepreferably about 1 to 25% by weight in the reservoir in a transdermaldrug delivery device of the present invention. As used herein, the term“combination” when refers to selection of two or more chemicals meansthe chemicals are selected together and not necessarily that they bechemically combined together in a reaction.

In some embodiments, especially for drugs that do not transdermallypermeate readily, a large amount of permeation enhancer may be needed toaid the drug in transdermal delivery. The present invention isespecially suitable for such transdermal delivery systems. In suchcases, one or more permeation enhancers, alone or in combination, andwhich may include dissolution assistants, can constitute about 5 to 40%by weight, preferably about 10 to 35% by weight, and more preferablyabout 15 to 30% by weight solids of the resulting reservoir that hasadequate pressure sensitive adhesive properties.

In certain embodiments, optionally, certain other plasticizer ortackifying agent is incorporated in the polyacrylate composition toimprove the adhesive characteristics. Examples of suitable tackifyingagents include, but are not limited to, aliphatic hydrocarbons; aromatichydrocarbons; hydrogenated esters; polyterpenes; hydrogenated woodresins; tackifying resins such as ESCOREZ, aliphatic hydrocarbon resinsmade from cationic polymerization of petrochemical feedstocks or thethermal polymerization and subsequent hydrogenation of petrochemicalfeedstocks, rosin ester tackifiers, and the like; mineral oil andcombinations thereof. The tackifying agent employed should be compatiblewith the polymer or blend of polymers.

Transdermal delivery patches typically have protective layers. Forexample, as shown in FIGS. 1 and 2, the patch 1 further includes apeelable protective layer 5. The protective layer 5 is made of apolymeric material that may be optionally metallized. Examples of thepolymeric materials include polyurethane, polyvinyl acetate,polyvinylidene chloride, polypropylene, polycarbonate, polystyrene,polyethylene, polyethylene terephthalate, polybutylene terephthalate,paper, and the like, and a combination thereof. In preferredembodiments, the protective layer includes a siliconized polyestersheet.

A wide variety of materials that can be used for fabricating the variouslayers of the transdermal delivery patches according to this inventionhave been described above. It is contemplated that the use of materialsother than those specifically disclosed herein, including those whichmay hereafter become known to the art to be capable of performing thenecessary functions is practicable.

With patches made with acrylate polymers of the present invention, toassess transdermal flux of a drug from a patch, flux can be measuredwith a standard procedure using Franz cells or using an array offormulations. Flux experiments are done on isolated human cadaverepidermis. With Franz cells, in each Franz diffusion cell a disc ofepidermis is placed on the receptor compartment. A transdermal deliverysystem is placed over the diffusion area (1.98 cm²) in the center of thereceptor. The donor compartment is then added and clamped to theassembly. At time 0, receptor medium solution (between 21 and 24 ml,exactly measured) is added into the receptor compartment and the cellmaintained at 35° C. This temperature yields a skin surface temperatureof 30-32° C. Samples of the receptor compartment are taken periodicallyto determine the skin flux and analyzed by HPLC. In testing flux with anarray of transdermal miniature patches, formulations are prepared bymixing stock solutions of each of the mixture components of formulationin organic solvents (about 15 wt % solids), followed by a mixingprocess. The mixtures are then aliquoted onto arrays as 4-mm diameterdrops and allowed to dry, leaving behind solid samples or “dots.” (i.e.,mini-patches). The miniature patches in the arrays are then testedindividually for skin flux using a permeation array, whose principle ofdrug flux from a formulation patch through epidermis to a compartment ofreceptor medium is similar to that of Franz cells (an array of miniaturecells). The test array has a plurality of cells, a piece of isolatedhuman epidermis large enough to cover the whole array, and a multiplewell plate with wells acting as the receptor compartments filled withreceptor medium. The assembled permeation arrays are stored at 32° C.and 60% relative humidity for the duration of the permeationexperiments. Receptor fluid is auto-sampled from each of the permeationwells at regular intervals and then measured by HPLC for flux of thedrug.

Administration of the Drug

On application of the transdermal device (patch) to the skin of anindividual in need thereof, the drug in the drug reservoir of thetransdermal patch diffuses into the skin where it is absorbed into thebloodstream to produce a systemic therapeutic effect. The onset of thetherapeutic depends on various factors, such as, potency of the drug,the solubility and diffusivity of the drug in the skin, thickness of theskin, concentration of the drug within the skin application site,concentration of the drug in the drug reservoir, and the like.Typically, it is preferable that a patient experiences an adequateeffect within a few hours (e.g., 3-6 hours) of initial application.However, this is significant only on the initial application. Onrepeated sequential applications, the residual drug in the applicationsite of the patch is absorbed by the body at approximately the same ratethat drug from the new patch is absorbed into the new application area.Thus the patient should not experience any interruption of thetherapeutic effect, such as analgesia. When the patch is removed, thetherapeutic effect continues until the amount of residual drug in theskin is reduced and the drug cleared from the systemic circulation viavarious metabolic pathways.

When continuous therapeutic effect is desired the used patch would beremoved and a fresh patch is applied to a new location. For example, theused patch would be sequentially removed and replaced with a fresh patchat the end of the administration period to provide continual therapeuticeffect. Since absorption of the drug from the fresh patch into the newapplication area usually occurs at substantially the same rate asabsorption by the body of the residual drug within the previousapplication site of the patch, blood levels will remain substantiallyconstant.

Depending on the drug to be delivered, administration of a patch can bemaintained for a few days, e.g., at least three days, and up to 7 days,with 3-4 day regimen being considered preferable. In certain preferredembodiments, at least 3%, but not more than 40%, of the total amount ofthe drug in the patch is administered during approximately the first 24hours of use; at least 6%, but not more than 50%, of the total amount ofthe drug is administered during approximately the first 48 hours of use;and at least 10%, but not more than 75%, of the total amount of the drugis administered during the administration period.

Methods of Manufacture

The transdermal devices are manufactured according to known methodology.For example, in an embodiment, a solution of the polymeric reservoirmaterial, as described above, is added to a double planetary mixer,followed by addition of desired amounts of the drug, permeationenhancers, and other ingredients that may be needed. Preferably, thepolymeric reservoir material is an acrylate material. The acrylatematerial is solubilized in an organic solvent, e.g., ethanol, ethylacetate, hexane, and the like. The mixer is then closed and activatedfor a period of time to achieve acceptable uniformity of theingredients. The mixer is attached by means of connectors to a suitablecasting die located at one end of a casting/film drying line. The mixeris pressurized using nitrogen to feed solution to the casting die.Solution is cast as a wet film onto a moving siliconized polyester web.The web is drawn through the lines and a series of ovens are used toevaporate the casting solvent to acceptable residual limits. The driedreservoir film is then laminated to a selected backing membrane and thelaminate is wound onto the take-up rolls. In subsequent operations,individual transdermal patches are die-cut, separated and unit-packagedusing suitable pouchstock. Patches are placed in cartons usingconventional equipment. In another process, the drug reservoir can beformed using dry-blending and thermal film-forming using equipment knownin the art. Preferably, the materials are dry blended and extruded usinga slot die followed by calendering to an appropriate thickness.

EXAMPLES

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.In the following examples all percentages are by weight unless notedotherwise. T_(g) was determined by DSC (Differential ScanningCalorimetry) with 10° C./min heating rate. Modulus G′ is storage modulusat 25° C. and 1 rad/s frequency (Frequency sweep experiment wasconducted using AR-2000 rheometer from TA Instruments (TA Instruments,109 Lukens Drive, New Castle, Del. 19720). The test conditions were:strain 1%, temperature 25° C., frequency range 0.1 to 100 rad/s, gaparound 1000 micron). Creep compliance tests were conducted using AR-2000rheometer from TA Instruments. The test conditions were: stress 1000dyn/cm², temperature 30° C., time 3600 seconds, gap around 1000 microns.One skilled in the art will know how to measure T_(g), creep compliance,and storage modulus in view of the present disclosure.

Transdermal flux can be measured with a standard procedure using Franzcells or using an array of formulations. Flux experiments were done onisolated human cadaver epidermis. With Franz cells, in each Franzdiffusion cell a disc of epidermis is placed on the receptorcompartment. A transdermal delivery system is placed over the diffusionarea (1.98 cm²) in the center of the receptor. The donor compartment isthen added and clamped to the assembly. At time 0, receptor mediumsolution (between 21 and 24 ml, exactly measured) is added into thereceptor compartment and the cell maintained at 35° C. This temperatureyields a skin surface temperature of 30-32° C. Samples of the receptorcompartment are taken periodically to determine the skin flux andanalyzed by HPLC. In testing flux with an array of transdermal miniaturepatches, formulations are prepared by mixing stock solutions of each ofthe mixture components of formulation in organic solvents (about 15 wt %solids), followed by a mixing process. The mixtures are then aliquotedonto arrays as 4-mm diameter drops and allowed to dry, leaving behindsolid samples or “dots.” (i.e., mini-patches). The miniature patches inthe arrays are then tested individually for skin flux using a permeationarray, whose principle of drug flux from a formulation patch throughepidermis to a compartment of receptor medium is similar to that ofFranz cells (an array of miniature cells). The test array has aplurality of cells, a piece of isolated human epidermis large enough tocover the whole array, and a multiple well plate with wells acting asthe receptor compartments filled with receptor medium. The assembledpermeation arrays are stored at 32° C. and 60% relative humidity for theduration of the permeation experiments. Receptor fluid is auto-sampledfrom each of the permeation wells at regular intervals and then measuredby HPLC for flux of the drug.

Example 1

A monomer mix containing butyl acrylate, 2-hydroxyethyl acrylate,t-octyl acrylamide, acrylic acid, ethyl acetate (solvent), and2,2′-azobisisobutyronitrile (AIBN) (polymerization initiator) wasprepared. A fraction was charged to an appropriate vessel and heated toreflux with stirring. The remainder was added to the vessel over time.The ratios of the monomers and initiator added totally, i.e., butylacrylate:2-hydroxyethyl acrylate:t-octyl acrylamide:acrylic acid:AIBNwere 59:25.5:9.5:6:2. The material was then held at reflux for asuitable period of time. At the end of the hold period, the contentswere cooled to room temperature and the solution polymer discharged. Thedry film made from this polyacrylate formulation had storage modulus ofaround 9×10⁵ dyn/cm², creep compliance of around 7×10⁻⁵ cm²/dyn, andglass transition temperature of −8° C., and consequently was too stiffto provide adequate adhesive properties alone. This formed aproadhesive.

Example 2

A monomer mix containing butyl acrylate, 2-hydroxypropyl acrylate,t-octyl acrylamide, acrylic acid, ethyl acetate (solvent), and2,2′-azobisisobutyronitrile (AIBN) (polymerization initiator) wasprepared. A fraction was charged to an appropriate vessel and heated toreflux with stirring. The remainder was added to the vessel over time.The material was held at reflux for a suitable period of time. Theratios of the monomers and initiator added totally, i.e., butylacrylate: 2-hydroxypropyl acrylate:t-octyl acrylamide:acrylic acid:AIBNwere 59:25.5:9.5:6:2. At the end of the hold period, the contents werecooled to room temperature and the solution polymer discharged. The dryfilm made from this polyacrylate formulation had storage modulus ofaround 8×10⁵ dyn/cm², creep compliance of around 4×10⁻⁵ cm²/dyn, andglass transition temperature of −8° C., and consequently was too stiffto provide adequate adhesive properties alone. This formed aproadhesive.

Example 3

A monomer mix containing vinyl acetate, 2-hydroxyethyl acrylate,2-ethylhexyl acrylate, ethyl acetate (solvent), and2,2′-azobisisobutyronitrile (AIBN) (polymerization initiator) wasprepared. A fraction was charged to an appropriate vessel and heated toreflux with stirring. The remainder was added to the vessel over time.The material was held at reflux for a suitable period of time. Theratios of the monomers and initiator added totally, i.e., vinylacetate:2-hydroxyethyl acrylate:2-ethylhexyl acrylate:AIBN were50:10:40:1.2. At the end of the hold period, the contents were cooled toroom temperature and the solution polymer discharged. The dry film madefrom this polyacrylate formulation had storage modulus of around 2×10⁶dyn/cm², creep compliance of around 4×10⁻⁶ cm²/dyn, and glass transitiontemperature of −14° C., and consequently was too stiff to provideadequate adhesive properties alone. This formed a proadhesive.

Example 4

A monomer mix containing vinyl acetate, 2-hydroxyethyl acrylate,2-ethylhexyl acrylate, ethyl acetate (solvent), and2,2′-azobisisobutyronitrile (AIBN) (polymerization initiator) wasprepared. A fraction was charged to an appropriate vessel and heated toreflux with stirring. The remainder was added to the vessel over time.The ratios of the monomers and initiator added totally, i.e., vinylacetate:2-hydroxyethyl acrylate:2-ethylhexyl acrylate:AIBN were60:20:20:1.2. The material was held at reflux for a suitable period oftime. At the end of the hold period, the contents were cooled to roomtemperature and the solution polymer discharged. The dry film made fromthis polyacrylate formulation had storage modulus of around 4×10⁶dyn/cm², creep compliance of around 2×10⁻⁶ cm²/dyn, and glass transitiontemperature of −8° C., and consequently was too stiff to provideadequate adhesive properties alone. This formed a proadhesive.

Example 5

Polyacrylate adhesive DURO-TAK® 87-2287, (from National Starch &.Chemical Co.) and proadhesives from EXAMPLE 3 and EXAMPLE 4 wereanalyzed with and without permeation enhancers. The data in Table 1clearly demonstrate the effect of enhancer on the properties of currentcommercial acrylic adhesive as well as the novel polyacrylatecompositions described in this application. DURO-TAK® 87-2287 adhesivewith a T_(g) of −34° C. had severe cold flow at 20% lauryl lactateloading level. (The monomeric components of DURO-TAK® 87-2287 are mostlyvinyl acetate, 2-ethylhexyl acrylate, and hydroxyethyl acrylate.) Suchcold flow phenomenon is the reason this adhesive and most similarcommercial pressure sensitive adhesive systems are not suitable forapplications where relatively high loadings of enhancers are needed. LLis enhancer lauryl lactate. DURO-TAK® 87-2287 had unacceptablerheological properties (severe cold flow) for transdermal application inthe presence of 20% lauryl lactate. (Based on this invention, it wasalso found that many other PSA's with T_(g) creep compliance and storagemodulus similar to DURO-TAK® 87-2287 in the range suitable for PSA as iswould behave similarly). The data in Table 1 demonstrated that thecurrent commercial acrylate PSA were not suitable for applications wherehigh loading of enhancers is needed. It was found that transdermalpatches started to have undesirable rheological properties, such as thetendency to cold flow and low cohesive strength, when creep complianceis larger than 6×10⁻⁴ cm²/dyn. It has been found that typically for theprior commercial transdermal PSAs, enhancer loading is usually less than20% due to the impact of enhancer on PSA rheological properties.

The improvement of enhancer tolerance using the novel polyacrylatecomposition described in this application can also be seen from the datain Table 1. By increasing the ratio of hard to soft monomer in theformulation, the glass transition temperatures were increased. Themolecular weight was also increased. As a result, the polyacrylatecompositions described in EXAMPLES 3 and 4 had higher modulus and lowercreep compliance as can be seen from the data in Table 1. This resultedin polyacrylate compositions not suitable for pressure sensitiveadhesive application in pure form due to high modulus. However, thesepolyacrylate compositions had better enhancer tolerance. As a result,the compositions after the addition of 35 wt % LL had the desiredrheological properties for transdermal application. As can be seen fromthe data in Table 1, desirable creep compliance was still present whenenhancer loading was 35 wt %.

Further, the data in Table 2 showed that when compared to anothercurrently available commercial pressure sensitive adhesive DURO-TAK®87-4287, the polyacrelate from Example 3 provides better enhancertolerance.

TABLE 1 Effect of enhancer lauryl lactate (LL) on adhesive properties.Creep Modulus G′, compliance, Sample T_(g), ° C. dyn/cm² cm²/dynDURO-TAK ® 87-2287 −34 2.1 × 10⁵ 1.3 × 10⁻⁴ Polyacrylate composition −142.0 × 10⁶ 4.0 × 10⁻⁶ from EXAMPLE 3 Polyacrylate composition −8 4.0 ×10⁶ 2.0 × 10⁻⁶ from EXAMPLE 4 20 wt % LL in DURO- — 5.6 × 10⁴ 1.84 ×10⁻³ TAK ® 87-2287 34 wt % LL in Polyacrylate — 1.0 × 10⁵ 3.2 × 10⁻⁴composition from EXAMPLE 3 35 wt % LL in Polyacrylate — 1.2 × 10⁵ 4.0 ×10⁻⁴ composition from EXAMPLE 4

TABLE 2 Effect of enhancer oleic acid (OA) on adhesive properties. CreepModulus G′, compliance, Sample T_(g), ° C. dyn/cm² cm²/dyn DURO-TAK ®87-4287 −34 3.4 × 10⁵ 4.3 × 10⁻⁵ Polyacrylate composition from −14 2.0 ×10⁶ 4.0 × 10⁻⁶ EXAMPLE 3 25 wt % OA in DURO-TAK ® — 4.9 × 10⁴ 9.1 × 10⁻⁴87-4287 35 wt % OA in Polyacrylate — 6.1 × 10⁴ 2.0 × 10⁻⁴ compositionfrom EXAMPLE 3

Specific examples of various transdermal patches of the invention thatare capable of administering drugs for extended periods of time will bedescribed in the examples below. The adhesive-reservoir patches in whichthe reservoir includes a single phase polymeric composition of freeundissolved components containing an therapeutically effective amount ofdrug at subsaturation concentration are preferred.

Example 6

A transdermal patch containing active substance galantamine wereprepared as follows:

91.6 g polyacrylate solution (a 34.53 wt % solution of the polyacrylatedescribed in EXAMPLE 1), 13.5 g galantamine, 3.0 g lauric acid, 2.3 glauryl pyrrolidone, and 4.6 g oleic acid were mixed and homogenized. Thesolution was spread at a thickness of 12-15 mil (0.3-0.375 mm) on asiliconized PET film that is about 2-3 mil (0.05-0.075 mm) thick. Themass was dried at 65° C. over a period of 90 minutes. After solventevaporation, a 2-3 mil (0.05-0.075 mm) thick PET backing layer waslaminated on to the adhesive drug reservoir layer using standardprocedures. Individual patches with different size were die-cut fromthis laminate. It was found that the polyacryalte adhesive in theresulting patch had desirable storage modulus of around 2.1×10⁵ dyn/cm²,and desirable creep compliance of around 4.1×10⁻⁴ cm²/dyn.Comparatively, the polyacrylate without the drug and the enhancers hadglass transition temperature of −8° C., storage modulus of around9×10⁵dyn/cm², and creep compliance of around 7×10⁻⁵ cm²/dyn, and was toostiff and had inadequate adhesive properties. It was found that thepatches could deliver galantamine through cadaver skin in a Franz cellat a flux rate of 8.9 μg/cm²·hr. This shows such plolyacrylate can bemade into patches for galantamine therapy, e.g., for dementia, Alzheimerdisease, etc.

Example 7

A 99.8 g polyacrylate solution (about 36.92 wt % of polyacrylatedescribed in EXAMPLE 2), 15.6 g galantamine, 12.1 g oleic acid, and 1.0g lauric acid were mixed and homogenized. The resulting solution wasspread at a thickness of 10-12 mil on a silicone-coated PET film about2-3 mil (0.05-0.075 mm) thick. The mass was dried at 65° C. over aperiod of 90 minutes. After solvent evaporation, a 2-3 mil (0.05-0.075mm) thick PET backing layer was laminated on to the adhesive drugreservoir layer using standard procedures. Individual patches withdifferent size were die-cut from this laminate. It was found that thepolyacrylate adhesive in the resulting patch had desirable storagemodulus of around 3.2×10⁵ dyn/cm², and desirable creep compliance ofaround 2.2×10⁻⁴ cm²/dyn. Comparatively, the polyacrylate without thedrug and the enhancers had glass transition temperature of −8° C.,storage modulus of around 9×10⁵ dyn/cm² and creep compliance of around7×10⁻⁵ cm²/dyn, and was too stiff and had inadequate adhesiveproperties. It was found that the patches can deliver galantaminethrough cadaver skin in a Franz cell at a flux rate of 10.9 μg/cm²·hr.This shows such plolyacrylate can be made into patches for galantaminetherapy, e.g., for dementia, Alzheimer disease, etc.

Example 8

A transdermal patch containing active substance norelgestromin wereprepared as follows:

A 100.0 g polyacrylate solution (about 42.9 wt % of polyacrylatedescribed in EXAMPLE 3), 3.6 g norelgestromin, 7.8 g GMO, and 1.7 g NLSwere mixed and homogenized. The resulting solution was spread at athickness of 10-12 mil on a silicone-coated PET film of about 2-3 mil(0.05-0.075 mm) thickness. The mass was dried at 65° C. over a period of90 minutes. After solvent evaporation, a 2-3 mil (0.05-0.075 mm) thickPET backing layer was laminated on to the adhesive drug reservoir layerusing standard procedures. Individual patches with different size weredie-cut from this laminate. It was found that the polyacrylate adhesivein the resulting patch had desirable storage modulus of around 3.1×10⁵dyn/cm² and desirable creep compliance of around 6.2×10⁻⁵ cm²/dyn.Comparatively, the polyacrylate without the drug and the enhancers had astorage modulus of around 4×10⁶ dyn/cm² and a creep compliance of around2×10⁻⁶ cm²/dyn and was too stiff and had inadequate adhesive properties.Further, it has been shown that the polyacrylate of EXAMPLE 3 afterincorporating a large amount of permeation enhancer into a single phase(see Table 1), although without the drug, had adequate PSA properties.It was found that the patches were able to deliver norelgestrorninthrough cadaver skin in a Franz cell at a flux rate of 0.4 μg/cm²·hr.This shows such plolyacrylate can be made into patches fornorelgestromin therapy, e.g., for hormone replacement, birth control,etc.

Example 9

Nicotine hexanoate (200 grams) is added to 10 Kg of a solution of thepolyacrylate of Example 2 (from National Starch & Chemicals,Bridgewater, N.J.) in a blended solvent mixture of isopropyl alcohol (13wt %) and 87 wt % ethyl acetate to result in a 20 wt % solids insolvent(s) solution. This polyacrylate is a polar copolymer andconsisted of 26 wt % hydroxyl monomer, 6 wt % monomer with carboxylicacid groups, t-octyl acrylamide, and butyl acrylate. The solution ismixed well and was transferred to a pressurized casting vessel. Thissolution is fed to a casting head set up to lay down a 0.25 mm wetthickness film onto a moving web of siliconized polyester, 0.075 mmthick. The film is moved at a rate of about 5 feet per minute through aseries of three ovens 30 feet long. The ovens are set at 45 degrees °C., 85° C. and 95° C., with a total residence time of six minutes. Afterexiting the ovens, the films would contain typically less than 500 ppmof residual solvent(s). After exiting the ovens, a transdermal backingis laminated to the reverse side of the polyacrylate adhesive. Thebacking was a 0.05 mm thick layer of linear low density polyethylene.Individual systems of about 3 cm² are cut and the flux of which istested. It is expected that they have acceptable flux and that suchplolyacrylate can be made into patches for nicotine therapy, e.g., forsmoking cessation.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods used by those in pharmaceutical productdevelopment within those of skill of the art. Embodiments of the presentinvention have been described with specificity. The embodiments areintended to be illustrative in all respects, rather than restrictive, ofthe present invention. It is to be understood that various combinationsand permutations of various parts and components of the schemesdisclosed herein can be implemented by one skilled in the art withoutdeparting from the scope of the present invention. Further, where asubstance is described to comprise certain ingredients, it iscontemplated that a substance also be made consisting essentially of theingredients.

1-32. (canceled)
 33. A device for transdermal administration of at leastone drug, the device comprising: a reservoir matrix comprising: at leastone permeation enhancer; and an acrylate polymer, the acrylate polymerhaving a T_(g) of greater than −15° C. if without the at least one drugand without the at least one permeation enhancer, wherein the acrylatepolymer constitutes 40 wt % to 90 wt % of the matrix, the acrylatepolymer comprising soft monomer in an amount of up to 60 wt % of theacrylate polymer, hard monomer in an amount of at least 40 wt % of theacrylate polymer, and functional monomer in an amount of between 10 wt %to 35 wt % of the acrylate polymer, and wherein the at least one drugand the at least one permeation enhancer are dissolved in the acrylatepolymer.
 34. The device of claim 33, wherein the soft monomer is analkyl acrylate monomer having 4 to 10 carbon atoms in the alkyl group.35. The device of claim 33, wherein the soft monomer is selected fromthe group consisting of butyl acrylate, hexyl acrylate, 2-ethylhexylacrylate, octyl acrylate, dodecyl acrylate, and isomers thereof.
 36. Thedevice of claim 33, wherein the acrylate polymer constitutes 45 wt to 80wt % of the matrix.
 37. The device of claim 33, wherein the acrylatepolymer has a T_(g) of greater than −10° C. if without the at least onedrug and without the at least one permeation enhancer.
 38. The device ofclaim 33, wherein the matrix has a T_(g) in the range of −10° C. to −20°C., a creep compliance of less than 1×10⁻³ cm²/dyn, and a storagemodulus in the range of 1×10⁵ dyn/cm² to 8×10⁵ dyn/cm².
 39. The deviceof claim 33, wherein the matrix has a T_(g) in the range of −10° C to−40° C., a creep compliance in the range of 1×10⁻⁴ cm²/dyn to 6×10⁻⁴cm²/dyn, and a storage modulus in the range of 1×10⁵ dyn/cm² to 8×10⁵dyn/cm².
 40. The device of claim 33, wherein the at least one drug isselected from the group consisting of fentanyl, fentanyl analog,galantamine, norelgestromin, and salts and esters thereof.
 41. Atransdermal drug delivery device, comprising: a reservoir matrixcomprising: at least one drug dissolved in an acrylate polymer, theacrylate polymer having a T_(g) of greater than −15° C. if without theat least one drug, wherein the acrylate polymer constitutes 40 wt % to90 wt % of the matrix, the acrylate polymer comprising soft monomer inan amount of up to 60 wt % of the acrylate polymer, hard monomer in anamount of at least 40 wt % of the acrylate polymer, and functionalmonomer in an amount of between 10 wt % to 35 wt % of the acrylatepolymer.
 42. The device of claim 41, wherein the soft monomer is analkyl acrylate monomer having 4 to 10 carbon atoms in the alkyl group.43. The device of claim 41, wherein the acrylate polymer has a T_(g) ofgreater than −10° C. if without the at least one drug.
 44. The device ofclaim 41, wherein the matrix has a T_(g) in the range of −10° C. to −20°C., a creep compliance of less than 1×10⁻³ cm²/dyn, and a storagemodulus in the range of 1×10⁵ dyn/cm² to 8×10⁵ dyn/cm².
 45. The deviceof claim 41, wherein the matrix has a T_(g) in the range of −10° C. to−40° C., a creep compliance in the range of 1×10⁻⁴ cm²/dyn to 6×10⁻⁴cm²/dyn, and a storage modulus in the range of 1×10⁵ dyn/cm² to 8×10⁵dyn/cm².
 46. The device of claim 41, wherein the at least one drug isselected from the group consisting of fentanyl, fentanyl analog,galantamine, norelgestromin, and salts and esters thereof.
 47. Atransdermal drug delivery device, comprising: a reservoir matrixcomprising: at least one drug; at least one permeation enhancer; and anacrylate polymer comprising soft monomer in an amount of up to 60 wt %of the acrylate polymer, hard monomer in an amount of at least 40 wt %of the acrylate polymer, and functional monomer in an amount of between10 wt % to 35 wt % of the acrylate polymer, wherein the at least onedrug and the at least one permeation enhancer are dissolved in theacrylate polymer in a combined amount of at least 30 wt % of the matrix,and wherein the matrix is applicable as a pressure-sensitive adhesive toa body surface of a subject for transdermal delivery of the at least onedrug.
 48. The device of claim 47, wherein the acrylate polymer has aT_(g) of greater than −15° C. if without the at least one drug andwithout the at least one permeation enhancer.
 49. The device of claim47, wherein the acrylate polymer constitutes 40 wt % to 90 wt % of thematrix.
 50. The device of claim 47, wherein the matrix has a T_(g) inthe range of −10° C. to −20° C., a creep compliance of less than 1×10⁻³cm²/dyn, and a storage modulus in the range of 1×10⁵ dyn/cm² to 8×10⁵dyn/cm².
 51. The device of claim 47, wherein the matrix has a T_(g) inthe range of −10° C. to −40° C., a creep compliance in the range of1×10⁻⁴ cm²/dyn to 6×10⁻⁴ cm²/dyn, and a storage modulus in the range of1×10⁵ dyn/cm² to 8×10⁵ dyn/cm².
 52. The device of claim 47, wherein theat least one drug is selected from the group consisting of fentanyl,fentanyl analog, galantamine, norelgestromin, and salts and estersthereof.